Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

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Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from “strongly recommended” to “potentially useful”. Evidence-based “therapeutic reference ranges” and “dose related reference ranges” were elaborated after an extensive literature search and a structured internal review process. A “laboratory alert level” was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

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AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011

The selective serotonin reuptake inhibitors (SSRIs) have emerged as a major therapeutic advance in psychopharmacology. As a result, the discovery of these agents marks a milestone in neuropsychopharmacology and rational drug design, and has launched a new era in psychotropic drug development. Prior to the SSRIs, all psychotropic medications were the result of chance observation. In an attempt to develop a SSRI, researchers discovered a number of nontricyclic agents with amine-uptake inhibitory properties, acting on both noradrenergic and serotonergic neurons with considerable differences in potency. A given drug may affect one or more sites over its clinically relevant dosing range and may produce multiple and different clinical effects. The enhanced safety profile includes a reduced likelihood of pharmacodynamically mediated adverse drug-drug interactions by avoiding affects on sites that are not essential to the intended outcome. SSRIs were developed for inhibition of the neuronal uptake pump for serotonin (5-HT), a property shared with the TCAs, but without affecting the other various neuroreceptors or fast sodium channels. The therapeutic mechanism of action of SSRIs involves alteration in the 5-HT system. The plethora of biological substrates, receptors and pathways for 5-HT are candidates to mediate not only the therapeutic actions of SSRIs, but also their side effects. A hypothesis to explain these immediate side effects is that 5-HT is increased at specific 5-HT receptor subtypes in discrete regions of the body where the relevant physiologic processes are regulated. Marked differences exist between the SSRIs with regard to effects on specific cytochrome P450 (CYP) enzymes, and thus the likelihood of clinically important pharmacokinetic drug-drug interactions. Although no clear relationship exists between the clinical efficacy, plasma concentration of SSRIs, nor any threshold that defines toxic concentrations, but therapeutic drug monitoring (TDM) may be useful in special populations, such as in elderly patients, poor metabolizers (PM) of sparteine (CYP2D6) or mephenytoin (CYP2C19), and patients with liver and kidney impairment. Several meta-analyses have reviewed the comparative efficacy of TCAs and SSRIs, and concluded that both TCAs and SSRIs have similar efficacy in the treatment of depression. SSRIs have demonstrated better efficacy and tolerability in the treatment of obsessive compulsive disorder (OCD). They have also been found to be effective in the treatment for social anxiety disorder both in reducing total levels of social anxiety and in improving overall clinical condition. The benefit of SSRIs in anorexia nervosa (AN) is apparently short-term unless medication is given in the context of nutritional or behavioral therapy. No single antidepressant can ever be recommended for every patient, but in a vast majority of patients, SSRIs should be considered as one of the first-line drugs in the treatment of depression.

Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review.

Depression is one of the most common and debilitating psychiatric disorders and is a leading cause of suicide. Most people who become depressed will have multiple episodes, and some depressions are chronic. Persons with bipolar disorder will also have manic or hypomanic episodes. Given the recurrent nature of the disorder, it is important not just to treat the acute episode, but also to protect against its return and the onset of subsequent episodes. Several types of interventions have been shown to be efficacious in treating depression. The antidepressant medications are relatively safe and work for many patients, but there is no evidence that they reduce risk of recurrence once their use is terminated. The different medication classes are roughly comparable in efficacy, although some are easier to tolerate than are others. About half of all patients will respond to a given medication, and many of those who do not will respond to some other agent or to a combination of medications. Electro-convulsive therapy is particularly effective for the most severe and resistant depressions, but raises concerns about possible deleterious effects on memory and cognition. It is rarely used until a number of different medications have been tried. Although it is still unclear whether traditional psychodynamic approaches are effective in treating depression, interpersonal psychotherapy (IPT) has fared well in controlled comparisons with medications and other types of psychotherapies. It also appears to have a delayed effect that improves the quality of social relationships and interpersonal skills. It has been shown to reduce acute distress and to prevent relapse and recurrence so long as it is continued or maintained. Treatment combining IPT with medication retains the quick results of pharmacotherapy and the greater interpersonal breadth of IPT, as well as boosting response in patients who are otherwise more difficult to treat. The main problem is that IPT has only recently entered clinical practice and is not widely available to those in need. Cognitive behavior therapy (CBT) also appears to be efficacious in treating depression, and recent studies suggest that it can work for even severe depressions in the hands of experienced therapists. Not only can CBT relieve acute distress, but it also appears to reduce risk for the return of symptoms as long as it is continued or maintained. Moreover, it appears to have an enduring effect that reduces risk for relapse or recurrence long after treatment is over. Combined treatment with medication and CBT appears to be as efficacious as treatment with medication alone and to retain the enduring effects of CBT. There also are indications that the same strategies used to reduce risk in psychiatric patients following successful treatment can be used to prevent the initial onset of depression in persons at risk. More purely behavioral interventions have been studied less than the cognitive therapies, but have performed well in recent trials and exhibit many of the benefits of cognitive therapy. Mood stabilizers like lithium or the anticonvulsants form the core treatment for bipolar disorder, but there is a growing recognition that the outcomes produced by modern pharmacology are not sufficient. Both IPT and CBT show promise as adjuncts to medication with such patients. The same is true for family-focused therapy, which is designed to reduce interpersonal conflict in the family. Clearly, more needs to be done with respect to treatment of the bipolar disorders. Good medical management of depression can be hard to find, and the empirically supported psychotherapies are still not widely practiced. As a consequence, many patients do not have access to adequate treatment. Moreover, not everyone responds to the existing interventions, and not enough is known about what to do for people who are not helped by treatment. Although great strides have been made over the past few decades, much remains to be done with respect to the treatment of depression and the bipolar disorders.

http://journals.sagepub.com/doi/pdf/10.1111/1529-1006.00008

Treatment and Prevention of Depression

Objectives. This 2013 update of the practice guidelines for the biological treatment of unipolar depressive disorders was developed by an international Task Force of the World Federation of Societi...

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World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Update 2013 on the Acute and Continuation Treatment of Unipolar Depressive Disorders

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCAs) is a cost-effective tool to increase efficacy and safety in patients suffering from major depressive illness. The concentration:antidepressant response relationships of nortriptyline, desipramine, and amitriptyline conform to a curvilinear relationship between concentration:antidepressant response; whereas, imipramine conforms to a linear relationship. Besides improving efficacy, TDM identifies the subset of patients who are at risk to develop excessive plasma TCA levels with potential resultant central nervous system and cardiovascular toxicity. Taking both the efficacy and safety data into account, cost:benefit analyses demonstrate that TDM is cost effective when used once as a standard aspect of care in the TCA treatment of patients with major depressive illness.

Gary A. Fast

Papers

Therapeutic drug monitoring for antidepressants: Efficacy, safety, and cost effectiveness.

Therapeutic drug monitoring. Principles and practice.